Project Summary Abstract Sudden cardiac death is a major cause of death around the world, with nearly 450,000 sudden deaths per year in the United States. Ventricular fibrillation (VF) is the most frequent direct cause. The most common strategy for terminating VF is with a single, large, biphasic high-energy (HE) electric shock by an implantable cardiac defibrillator (ICD). Despite their effectiveness, there have been increasing concerns with current ICD high- energy therapy, due to cardiac tissue damage likely a result of high voltage shocks and pain caused by inappropriate shocks. Redesign and optimization of shock waveforms is critical for developing a low-energy defibrillator that will be more acceptable to patients and clinicians. We aim to develop implantable low-energy defibrillators to address unmet needs for treating cardiac rhythm disorders. The ?virtual electrode polarization? (VEP) concept has been proposed as a mechanism responsible for termination of atrial fibrillation (AF) and demonstrated in experimental optical mapping studies in vitro and in vivo. Recent canine studies and human results have revealed that Unpinning Termination (UPT) therapy for atrial fibrillation significantly lowers the energy required for atrial defibrillation. Mechanistically it is explained as: (1) unpinning of reentrant wave fronts that maintain AF, (2) preventing re-pinning of wave fronts to tissue heterogeneities, such as scars, and (3) annihilating remaining wave fronts not self extinguished. The unpinning stage uses multiple pulses to unpin the reentry from the stabilizing resistive heterogeneity. The applied electric field creates stronger VEP at tissue heterogeneities, which causes excitation and then unpinning of the reentry. More recent animal findings from Cardialen?s Phase I STTR project indicate that UPT therapy is also highly effective as ventricular tachycardia (VT) therapy. To deliver and test this novel method clinically, an efficient cardioverter system is proposed in this Phase II SBIR project. Following development of this system, this Phase II SBIR project aims to confirm that UPT therapy can terminate ATP-refractory VT and VF with low energy in humans. It is anticipated that the proposed new study in humans will confirm fundamentally important insights into the hypothesis that multiple phased low-energy shocks can safely terminate ventricular tachycardia and ventricular fibrillation. We expect the study will be a big step forward from the ?VEP and unpinning? theory to ventricular defibrillator clinical development. If the enhanced research UPT therapy system is proven effective and safe for terminating ventricular tachyarrhythmias, it should advance commercial product development of low-energy multiple pulse implantable defibrillator devices and will also encourage a higher percentage of eligible patients to consider this life-saving treatment.